The clinical significance of tissue, blood and urine polyamine in renal cell carcinoma]

With the use of a newly developed and convenient enzymatic method, tissue, urine and blood polyamine (diamine, spermidine and spermine) levels were evaluated as a tumor marker of renal cell carcinoma (RCC) in 50 cases with the disease. Furthermore, blood and urine polyamines were periodically determined and evaluated as a follow-up marker. The pretreatment three polyamine levels in tissue, blood and urine of the patients were all significantly higher than those of the controls. However, because of their low sensitivities, they were not always decisive for biochemical diagnosis of RCC. Tissue spermidine levels were increased with the advance of the stages. Tissue diamine level also showed a good correlation with the pathological grade. Tissue diamine was found to predict distant metastasis. Blood spermidine and urine diamine were useful as follow-up markers. In conclusion, combined determination of tissue, blood and urine polyamine levels was thought to be useful as tumor markers of RCC.     

Polyamine levels and gastrin receptors in colon cancers.

Polyamines and gastrin receptors (GR) were studied in samples of colon cancer and mucosa from 40 patients and in control mucosa from 11 patients without cancer. Polyamines (i.e., putrescine, spermidine, spermine) are essential for growth and differentiation. The concentration of polyamines is elevated in rapidly proliferating normal tissues and in some cancers. The presence of GR in human colon cancers has been previously reported. The purpose of the present study was twofold: (1) to determine whether polyamine levels are elevated in colon cancers and in adjacent normal colon mucosa compared to colon mucosa from patients without cancer; and (2) to examine the relationship between polyamine levels and GR in colon cancers. Polyamine levels in colon cancers were significantly higher than in the normal colon mucosa from the same patients. The polyamines, spermidine and spermine, were significantly higher in colon mucosa from patients with cancer compared to patients without cancer. Spermidine and the spermidine:spermine ratio, an index of cell proliferation, were increased in colon cancers with GR compared to cancers without GR. There were no significant correlations between polyamine levels and the following: patient age, CEA level, site of cancer, stage, or differentiation. Because polyamine levels are increased in colon mucosa from patients with cancer, measurement of polyamines may detect patients at risk for subsequent development of colon cancer. Increased levels of polyamines in colon cancers with GR is evidence that gastrin may play a trophic role in human colon cancers.     

Polyamines in breast cancer

Polyamine levels (putrescine, spermidine and spermine) in breast cancers (n = 54) were measured as a potential guide to prognosis. Values (expressed as nmol per 100 mg tumour) ranged from: 0.9 to 4.5 for putrescine, 4.2 to 29.8 for spermidine and 5.6 to 39.7 for spermine concentration. Increased intracellular polyamine levels were positively correlated with factors known adversely to affect survival after mastectomy, namely histological grade III and oestrogen-receptor negative status. Advanced T4 tumours and medullary-type carcinomas also contained high polyamine levels. Tumour size and node status did not affect polyamine levels in primary tumours. Tumours that recurred within 2 years of mastectomy had significantly higher levels of spermidine and spermine than those that did not. Breast cancer polyamine levels are a biological marker of tumour aggressiveness and can be used as a prognostic indicator of early tumour recurrence that is independent of node status.     

The clinical value of urinary polyamine analysis in urological disease

To study the clinical usefulness of the determination of urinary polyamine levels, voluntary urine of several urological diseases including 56 bladder tumor patients was analyzed by high performance liquid chromatography. The obtained values were adjusted by the concentration of urinary creatinine and expressed as the unit of mumol/g creatinine (mumol/g Cr) From the measurement of 8 normal adults, the normal upper limit of each polyamine was decided by mean + 2SD, and the limit for total polyamine was 59.1 mumol/g Cr, putrescine 38.1 mumol/g Cr, spermidine 16.6 mumol/g Cr and spermine 9.2 mumol/g Cr, respectively. In the patients with non-neoplastic benign urological disease, the polyamine levels were statistically not different from those of the normal adults. In the case of bladder tumor, the urinary levels of total polyamine, putrescine and spermine were significantly elevated compared with the control group. The true positive rate of this determination in bladder tumor patients was 26/56 (46%) by total polyamine level, 21/56 (38%), by putrescine level, 11/56 (56%) by spermidine level and 16/56 (29%) by spermine level. Grade or stage of the bladder tumor did not have any significant correlation with the urinary polyamine level. This determination would not be included in routine clinical examinations due to the difficulty of measurement, difference of urine sampling and lack of high sensitivity and specificity.     

Red blood cell polyamines in brain tumour patients

Red blood cell polyamine levels have been determined in patients with various histologically confirmed brain tumours. Increased spermine and spermidine levels were found in most patients with perifocal oedema demonstrated by CT; no correlation was found to other CT variables, nor to tumour localization. Polyamine levels increased during the clinical course coincident with tumour activity and decreased in response to surgery and radiotherapy. The response to chemotherapy involved a change in the relationship between spermine and spermidine levels. Our results underline the significance of regular polyamine level estimation during the management of patients with brain tumours.     

Polyamines in colorectal cancer

Polyamine levels (putrescine, spermidine and spermine) in colorectal cancers (n = 25) were measured in order to assess their importance as markers of cellular proliferation. Colonic mucosa from healthy resection margins of patients with diverticular disease (n = 5) was used as control material. Polyamine levels (expressed as nanomoles per 100 mg tumour) in cancers ranged from 0.8 to 7.9 for putrescine (mean: 2.3 +/- 0.7), from 6.5 to 22.8 for spermidine (mean: 13.9 +/- 0.9) and from 13.0 to 37.5 for spermine (mean: 22.1 +/- 1.3). Mean spermidine and spermine content of cancers was more than three times mean spermidine (3.92 +/- 0.8), and more than four times mean spermine (5.0 +/- 1.2), content of normal colonic mucosa (P less than 0.01). Polyamine content of colorectal cancers was independent of tumour site, Dukes' stage, histological grade and the presence of palpable liver metastases at laparotomy. Because colorectal cancers contain such high levels of spermidine and spermine, polyamines may play an essential role in the regulation of their growth.     

Erythrocyte polyamine levels in human prostatic carcinoma.

Abnormally high red blood cell polyamine levels were found in benign prostatic hyperplasia and in prostatic adenocarcinoma patients. In prostatic adenocarcinoma patients a relationship was noted between the importance of red blood cell spermidine and spermine concentrations, and the clinical stage of the disease (Whitmore classification). Considering prostatic adenocarcinoma patient populations, patients with metastases (groups 3 and 4) statistically differed from those without metastases (group 2). Furthermore, red blood cell polyamine level determination discriminated patients in the hormonal escape group (group 4) from those usually considered as hormone responsive (groups 2 and 3). No statistically significant correlation was observed between red blood cell polyamine levels and usual tumor markers (prostatic acid phosphatase and prostate specific antigen). These results confirmed that red blood cell polyamine levels must be considered as a circulating index of cell proliferation that might be of clinical importance during the long-term followup and treatment of prostatic adenocarcinoma patients.     

Detection of urinary polyamine by a new enzymatic differential assay. (I). Fundamental study on a new enzymatic differential assay

A new enzymatic method for determining urinary polyamine concentration by fractionation of the urinary acetyl conjugate into free polyamines with acylpolyamine amido-hydrolase and quantification using two kinds of amine-oxidase of different substrate specificity was examined. High recovery rates of urinary polyamine by enzymatic hydrolyzation were obtained, namely, 95 +/- 4% for diamine, 95 +/- 1% for spermidine and 99 +/- 2% for spermine. Furthermore, excellent linearity was demonstrated with up to 150 mumole/l diamine, up to 75 mumole/l spermidine and up to 50 mumole/l spermine. Although urinary polyamine concentration varied diurnally even after correction of urinary creatinine, day-to-day variation disappeared. In 24-hour pooled urine and voluntary urine, diamine, spermidine and spermine correlated relatively well. Urinary leukocytes and erythrocytes exerted no influence on urinary polyamine.     

Detection of polyamines by a new enzymatic differential assay. (8) Studies on tissue polyamine concentrations in patients with genitourinary malignant diseases

Polyamine concentrations of human cancerous and non-cancerous tissues from the kidney, ureter, bladder were measured by a new enzymatic method for isolation and determination of polyamines. In cancerous and non-cancerous tissue of the organs studied, the spermine level was highest followed by the spermidine and diamine levels. The concentrations of diamine, spermidine and spermine in cancerous tissues were significantly higher than those in non-cancerous tissues, but there was no significant difference in the spermidine/spermine ratio between the cancerous and non-cancerous tissues. These data suggest that polyamines are produced above the normal levels in pathological conditions such as renal cell carcinoma, ureteral cancer and bladder cancer.     

Urine levels of polyamine in patients with or without cancer

The urine levels of polyamine (total amount of putrescine, spermidine and cadaverine) were measured in patients with or without cancer by simple enzymatic assay method. In 148 control healthy adults, the urine levels of polyamine were 23.1 +/- 7.1 mumole/g. creatinine, whereas among 52 patients with benign diseases, the level in only 5 patients was slightly higher than normal level. The polyamine levels in 170 patients with cancer was 46.1 +/- 50.6 mumole/g. creatinine, which was about 2-times higher than normal level. In the patients with cancer of the stomach or the colon and rectum, the increase in polyamine level appeared to be correlated with the clinical stage of tumor. Following successful surgical resection of cancer, the polyamine level increased in one week transitorily after operation but gradually decreased to normal level within 5 weeks. Whereas following unsuccessful surgical resection of cancer, the polyamine value maintained high levels. The evidence suggests that the measurement of the urine level of polyamine is useful for the diagnosis of cancer or the clinical stage of tumor, and it will be helpful in the evaluation of therapeutic effects and prognosis.     

The growth of MAT-LyLu rat prostatic adenocarcinoma can be prevented in vivo by polyamine deprivation

The combination of inhibitors of ornithine decarboxylase and polyamine oxidase, and of antibiotics suitable for the (partial) decontamination of the gastrointestinal tract, with a polyamine deficient diet, is responsible for the almost complete inhibition of the growth of MAT-LyLu prostatic adenocarcinoma. In the tumor-bearing animals, erythrocyte spermidine levels were reduced, but spermine concentrations were increased. As has been previously observed, the increase in erythrocyte spermine level was associated with an enhancement of malignant cell death. Adriamycin administration did neither diminish tumor growth, nor potentiate the antitumor effect of polyamine deprivation treatment. Interruption of the polyamine deprivation treatment was accompanied by a significant enhancement of tumor growth. Since polyamine deprivation causes only reversible growth inhibition, it seems not appropriate as a monotherapy.     

Ornithine decarboxylase activity and its gene expression are increased in benign hyperplastic prostate

BACKGROUND: Ornithine decarboxylase (ODC) is the first key enzyme in the polyamine biosynthesis pathway. Polyamine is believed to participate in cellular proliferation and differentiation. To study the relationship between ODC and the pathogenesis of benign prostatic hyperplasia (BPH), the polyamine levels, ODC activities, and expression of ODC mRNA in benign hyperplastic and normal human prostates were assayed. METHODS: Polyamine contents and ODC activities in tissue extracts were determined by reverse-phase high-performance liquid chromatography and spectrophotometric procedures, respectively. The ODC mRNA levels were assayed by Northern blot analysis. RESULTS: The contents of putrescine, spermidine, and spermine in BPH tissues were 2.2, 3.4, and 6.0 times higher than those in normal tissues, respectively; the ODC activity of BPH tissue was about 3.2 times higher than in normal tissue; the expression level of ODC mRNA in the BPH tissues was greater than that of normal tissues. CONCLUSIONS: The findings imply that 1) the increased ODC activity and polyamine content in prostatic tissue may correlate with the pathogenesis of BPH, and 2) the high level of ODC activity is induced by the overexpression of ODC mRNA.     

Effect of difluoromethylornithine on host and tumor polyamine metabolism during total parenteral nutrition

Clinical and experimental data suggest that erythrocyte (RBC) polyamine (PA) levels are markers of tumor proliferation during total parenteral nutrition (TPN). The purpose of this experiment was to determine whether the inhibition of PA synthesis during TPN was greater in tumors than in normal host tissue. Rats bearing a subcutaneous fibrosarcoma were randomized to receive a chow diet (n = 5), TPN (n = 5), or TPN + difluoromethylornithine (DFMO) (an irreversible inhibitor of ornithine decarboxylase (ODC), at 1000 mg/kg body wt/day n = 4) for 6 days by continuous central venous infusion. TPN + DFMO resulted in a higher plasma albumin level and lower tumor ODC activity compared with chow feeding or TPN. Liver ODC activity was similar for the chow fed, TPN, and TPN + DFMO groups. RBC putrescine, tumor putrescine, and tumor spermidine levels were significantly lower in the TPN + DFMO group compared with the chow fed and TPN groups. RBC spermidine, RBC spermine, and tumor spermine levels were significantly increased with TPN + DFMO compared with TPN alone. DFMO did not produce diarrhea or weight loss. Increased RBC spermidine may indicate a toxic effect of DFMO on the tumor, resulting in leakage of tumor spermidine into the extracellular space. The data suggest that DFMO during TPN can selectively inhibit tumor PA synthesis and may improve host utilization of nutrients.     

Transforming growth factor beta as a clinical biomarker for prostate cancer

ObjectivesTumor biomarkers to detect prostate cancer earlier may reduce prostate cancer deaths. Transforming growth factor-beta1 and -beta2 (TGF-beta1 and -beta2) become overexpressed in prostate cancer and might be useful tumor markers of prostate cancer.MethodsPlasma and urinary TGF-beta1 and plasma TGF-beta2 levels were studied preoperatively in 74 consecutive patients who had prostate cancer and underwent radical prostatectomy and were compared with those of 29 similarly aged male control patients who had no clinical evidence of prostate cancer.ResultsPlasma TGF-beta1 levels were similar in both prostate cancer and control groups and did not correlate with serum prostate-specific antigen (PSA), clinical and pathologic stages, or Gleason grade. Urinary TGF-beta 1 levels, however, increased 3.5-fold in patients with prostate cancer relative to controls and tended to be higher with advancing clinical and pathologic stages. Plasma TGF-beta2 levels, like plasma TGF-beta1 levels, were similar for both the study and control groups, but when stratified by pathologic stage or Gleason grade, patients with prostate cancer with pathologic Stage T2a and Gleason grade of 3 or less had significantly increased plasma TGF-beta2 levels as compared with either control patients or patients with prostate cancer with pathologic Stages T2b/T2c and T3/T4 or Gleason grade of 4 or more, suggesting that early prostate cancer may contribute to plasma TGF-beta2 levels.ConclusionsUnlike plasma TGF-beta1 levels, urinary TGF-beta1 and plasma TGF-beta2 levels were higher in patients with prostate cancer and may be useful biomarkers of prostate cancer. Copyright 1997 by Elsevier Science Inc. UROLOGY 49: 151-155, 1997.     

Polyamine metabolism in carcinoma of the oral cavity compared with adjacent and normal oral mucosa

In this study, polyamine biosynthesis required for cellular proliferation showed elevated levels in neoplastic cells. Putrescine, spermidine, and spermine, as well as the rate-limiting enzyme ornithine decarboxylase, were measured to evaluate differences in tissue concentration in squamous cell carcinoma of the oral cavity, and in the normal adjacent, buccal, and retromolar trigone tissues. Mean polyamine levels (nanomoles per gram of tissue +/- standard error of the mean) were significantly elevated in tumor tissue at 136 +/- 42 nmol/g for putrescine compared with 41 +/- 9 nmol/g in adjacent, 25 +/- 5 nmol/g in buccal, and 41 +/- 14 nmol/g in retromolar trigone tissues. Tumor spermidine was 415 +/- 41 nmol/g compared with 192 +/- 34 nmol/g in adjacent, 184 +/- 34 nmol/g in buccal, and 214 +/- 63 nmol/g in retromolar trigone tissues. Tumor spermine was 461 +/- 41 nmol/g compared with 236 +/- 30 nmol/g in adjacent, 233 +/- 35 nmol/g in buccal, and 269 +/- 59 nmol/g in retromolar trigone samples. Ornithine decarboxylase activity was highly variable in tumor tissues. High levels of polyamines appear to be specific for this malignancy, whereas ornithine decarboxylase activity is not. Measurement of polyamine content may be useful in evaluating epithelial changes in the oral cavity.     

血清脂联素与大肠癌关系的研究

目的 通过比较大肠癌患者和健康人脂联素在血清中的浓度,研究其与大肠癌之间的关系,为大肠癌的早期诊断和治疗做初步研究.方法 对38例大肠癌患者和38例健康人采取新鲜血清应用酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)测定脂联素的浓度,分析之间是否存在差异,及分析不同肿瘤组织病理分期、不同肿瘤大小等因素与脂联素浓度的关系.结果 大肠癌患者的血清脂联素水平159.89 ps/mL明显低于健康对照组184.5 pg/mL(P=0.001).P53的表达与患者血清脂联素水平无相关性(P=0.678).不同Dukes分期间的脂联素水平差异无统计学意义.但肿瘤超过5 cm的患者脂联素平均水平144.86 pg/mL,明显低于肿瘤小于5 cm患者脂联素平均水平178.47 pg/mL(P=0.04).结论 低水平的血清脂联素浓度与大肠癌发生有关,并且血清脂联素浓度与肿瘤大小有着负相关,可以推测脂联索在大肠癌的发生、发展过程中起重要作用.     

Prognostic value of plasma D-dimer levels in patients with colorectal cancer

Objective Plasma D‐dimer levels have been shown to be increased in patients with various solid tumours including lung, prostate, cervical, ovarian, breast and colon cancer. The purpose of this prospective study was to estimate the plasma D‐dimer level of patients with colorectal cancer before surgery and to assess whether it has a prognostic value. Method The study comprised 51 patients with colorectal cancer. Variables including demographic, clinical, operative and pathological findings and routine laboratory tests were recorded. In addition, tumour markers, coagulation tests and plasma D‐dimer levels were evaluated. Results Histological types other than well‐differentiated adenocarcinoma, relatively advanced tumour stage and a high preoperative plasma D‐dimer level were the prognostic factors that were associated with shorter postoperative survival according to univariate analyses. The presence of vascular invasion was associated with higher preoperative D‐dimer levels. However, there was no statistically significant relationship between postoperative survival and the presence of vascular invasion. Conclusion Postoperative survival was significantly shorter in colorectal cancer patients with elevated preoperative D‐dimer levels. Evaluation of preoperative D‐dimer level can be used to predict postoperative survival.     

Altered polyamine concentrations in cytomegalovirus-infected human cells

Polyamines have a regulatory effect on DNA and RNA synthesis and their levels are elevated in rapidly growing cells, including lymphoblasts. However, as shown in the current experiments, exposure to cytomegalovirus (CMV) reduces the polyamine levels in these cells, suggesting that the virus interferes with their metabolism. Studies have shown that the activity of ornithine decarboxylase is increased in CMV-infected fibroblasts and that there is an increased conversion of putrescine to spermidine and spermine. Thus it may be expected that the concentration of these molecules would increase in the infected cell. However, the results presented here demonstrate that only the concentrations of putrescine and spermidine are increased, the spermine concentration decreasing with infection.     

Plasma concentration of tissue inhibitor of matrix metalloproteinase 1 in patients with colorectal carcinoma.

BACKGROUND: The expression of tissue inhibitor of matrix metalloproteinase (TIMP) 1 in tumour tissue from patients with colorectal carcinoma has been reported to be related to disease progression. However, the clinical significance of plasma TIMP-1 has not been fully elucidated. METHODS: The plasma level of TIMP-1 protein was determined by enzyme-linked immunosorbent assay in samples from 54 patients who underwent resection of the primary tumour. RESULTS: Plasma TIMP-1 levels were associated significantly with depth of invasion and metastasis to lymph nodes and liver. Circulating TIMP-1 levels were significantly higher in patients with serosal invasion, liver metastases and Dukes' stage C tumours. Using a cut-off value of 160 ng/ml, serosal invasion and Dukes' C stage could be predicted with an accuracy of 68.5 per cent. With a cut-off value of 170 ng/ml, metastasis to the lymph node and liver could be predicted with an accuracy of 66.7 and 70.4 per cent respectively. These values were greater than those for carcinoembryonic antigen and CA19-9. CONCLUSION: These data suggest that the plasma concentration of TIMP-1 correlates with both invasion and metastasis in patients with colorectal carcinoma.     

脂联素、瘦素、抵抗素的表达对判断结直肠癌临床分期及预后的价值

目的:探讨结直肠癌组织中脂联素、瘦素、抵抗素表达水平与结直肠癌临床分期的关系及对预后判断的价值.方法:选取2015年2月-2016年2月收治的结直肠癌患者56例作为研究对象,术中收集癌组织和癌旁组织,另选取同期收治的行纤维结肠镜活检或切除并经病理证实的结直肠腺瘤患者52例为结直肠腺瘤组.分别采用免疫组织化学染色法和实时...